Feline infectious peritonitis
(FIP) is the leading infectious cause of cat death. FIP occurs when
the cat reacts inappropriately to feline coronavirus (FCoV) infection.
Most cats simply become infected, shed FCoV for a month or two,
mount an immune response, eliminate the virus and live happily ever
after (see How to eliminate FCoV infection from
a cattery or household of cats). However, for reasons that we don't yet fully understand,
instead of clearing FCoV infection, an unfortunate few cats develop
FIP..

The name FIP is slightly
misleading: FIP isn't inflammation of the peritoneum (the lining
of the abdomen) it is a vasculitis (inflammation of the blood vessels).
The clinical signs which the cat develops depend on which blood
vessels are damaged, and on which organ(s) the damaged blood vessels
supplied.

The key event in the development of FIP is the infection of the monocyte (a white blood cell) by feline coronavirus (FCoV). From the moment of infection of the monocyte, the cat’s fate hangs on whether or not that monocyte can contain the virus and eventually defeat it, or whether the virus wins, and begins replicating within the monocyte. In the animation shown below, we depict the latter. We show how the virus hijacks the immune system, leading to an inflammatory sequence of events which results in a pyogranuloma forming around a blood vessel. In the film we show the development of acute FIP, where there is a lot of virus, many blood vessels affected, and the resulting leakage from damaged blood vessels causes the clinical signs of effusive FIP – ascites, thoracic effusion, pericardial effusion.

In non-effusive FIP the course is more chronic: fewer blood vessels are affected, the cat’s immune system tries harder to contain the infection, leading to larger pyogranulomata and the clinical signs of chronic inflammation and relating to the organ(s) containing the pyogranulomas.

I am very grateful to Dr Francois Bagaini, of vetocyte.fr for making this animation for me:

Wet
or effusive FIP
This is the acute form of the disease, where many blood vessels
are damaged severely and fluid leaks out of them into the abdomen
or the thoracic (chest) cavity. When the blood vessels in the abdomen
are affected, the cat's tummy swells up with fluid called ascites.
When the blood vessels in the thorax are damaged fluid leaks into
the chest, impairing the ability of the lungs to expand and the
cat shows difficulty breathing.

The cat may bleed into the
eye, or white precipitates appear on the cornea (the clear membrane
on the front of the eye).

For vets: check the eyes
using an ophthalmoscope for vitreous flare and retinal vesselcuffing (see
photo below).

(Many thanks to John Mould
for this photograph.)

Around 12% of cats with non-effusive
FIP develop neurological signs: often they become ataxic (wobbly
and falling over when walking), they may have head tremors, fits,
their eyes may dart from side to side instead of being focussed.

However, all of these clinical
signs can be caused by other, sometimes treatable, conditions, which
is why accurate diagnosis is essential.

FIP is a notoriously
difficult condition to diagnose, many other conditions present with
very similar clinical signs. Definitive diagnosis is only possible
at post mortem, or occasionally by biopsy (though for accurate biopsy
results one has to actually biopsy a visible pyogranulomatous lesion,
which may necessitate laparotomy). Only 18% of samples sent to our
laboratory for FIP diagnosis turn out to be FIP. Since cats with
FIP are usually euthanased, it is absolutely vital that FIP is accurately
differentiated from other, treatable, conditions.

No matter what any laboratory or manufacturer of test kits claims, there is no single test for FIP – diagnosis is a challenge to even the most competent veterinary clinician and involves following a series of steps on an algorithm (download catvirus.com FIP flowchart). [The European Advisory Board of Cat Disease (ABCD) FIP algorithm was based on this flowchart (Addie et al, JFMS, 2009).] Diagnosing FIP
consists of a number of steps as shown in the flowchart. Until you have a lot of experience in diagnosing FIP, you might find it useful to use the chart, and also the catvirus.com FIP diagnosis worksheet.

There are usually 2 key aspects in the cat's history which suggest that FIP is a possible diagnosis of his or her presenting signs: first the cat MUST have become infected with feline coronavirus (FCoV) in order to have developed FIP, therefore there will be a history of having been in a multicat environment, such as at a cat breeder's, or a rescue shelter, within the previous 18 months. (Development of FIP more than 18 months after infection would be very unusual, though does occur in geriatric cats or immunosuppressed cats, e.g. cats undergoing chemotherapy, or cyclosporine A (Atopica, Novartis) treatment, or after becoming infected with feline leukaemia virus or feline immunodeficiency virus.

A cat living indoors alone all his or her life will be very unlikely to have developed FIP (though check for a history of having stayed in a boarding cattery, or some other opportunity for exposure – e.g. recent adoption of a kitten).

In addition, most cats with FIP have a history of having had a stress of some sort – being neutered, rehomed, the introduction of a new kitten, etc. Incubation for effusive FIP is usually a few days up to one month. The incubation period for non-effusive FIP can be up to a year. FIP is most common on first exposure to the virus - if a cat has been infected with FCoV for over a year, it is unlikely he or she will develop FIP.

Effusive FIP is the more acute condition – occurring within 4-6 weeks of a stressful event in the cat’s life, whereas non-effusive FIP can incubate for months to years. If you understand that FIP is an immune-mediated vasculitis it becomes easier to understand how it is able to manifest with so many varied clinical signs. Any blood vessel to any organ can be affected and the clinical signs will result from damage to that organ. In effusive FIP, many blood vessels are affected, allowing fluid to leak out into the abdomen, thorax or pericardium. Thus the cat presents with ascites or pleural or pericardial effusion. The ascitic cat may appear to have put on weight, although ribs are usually more palpable. The Orion Foundation call FIP “the purring disease” because the cat may still be bright and eating, though some are dull and anorexic. The temperature of cats with FIP rarely exceeds 103oF (39oC). A cat with a pleural effusion will present with dyspnoea.

To perform a Rivalta test, take 10 mls of water (must be at room temperature), add 2-3 drops of 8% acetic acid (ordinary clear/white vinegar) and carefully layer a drop of the effusion into it. If the effusion dissipates like a wisp of smoke in air the Rivalta test is negative and the cat is 97% not likely to have FIP. If, however, the effusion hangs from the surface in a globule, then slowly floats down like a jellyfish, the Rivalta test is positive. A positive Rivalta test means that the cat is 86% likely to have FIP (i.e. 5 of 6 cats with a positive Rivalta test do have FIP, so clearly other tests need to be performed to be more certain of the diagnosis).

Total protein in the effusion
and albumin:globulin ratio (A:G) The total protein concentration in the effusion of a cat with FIP is usually greater than 35 g/l and this usually consists of more globulin than albumin, pushing down the albumin to globulin (A:G) ratio. To calculate the A:G ratio, divide the albumin by the globulin values. An A:G of < 0.4 indicates FIP is quite likely; an A:G of >0.8 rules out FIP; A:G of between 0.4-0.8 is inconclusive - consider other parameters. The A:G of an effusion is one of the most useful tests to perform in practice for a quick indicator of whether or not a cat may have FIP and can be easily performed on an in-house biochemistry analyser machine.

Cytology
In effusive FIP, there are generally
less than 3 x 10 9 nucleated cells per litre in the effusion and
the cells are predominantly neutrophils and macrophages (see photograph below). In bacterial
peritonitis and pleurisy, the white blood cell count in the effusion
is much higher and the cytologist will usually see bacteria (if
they are intracellular, this indicates that they were not simply
contamination of the sample). Cytology of pleural effusions is useful
for differentiation of thymic lymphosarcomas, since the predominant
cell is the lymphocyte and they often appear malignant.

FCoV antibody titre
The presence of antibodies indicates
that the cat has been infected with FCoV, the cause of FIP. Any
FCoV antibody titre can occur in cases of wet or effusive FIP, but
most cats with FIP have extremely high antibody titres (1280 or
greater). Antibody titres of 0 are unusual in FIP cases and are
usually considered as indicating that the cat does not have FIP.
(However, if other parameters suggest a diagnosis of FIP,
despite having an antibody titre of 0, then this is the one situation
where FCoV RNA detection (RT-PCR), performed on a sample of the
effusion, is diagnostic of FIP. In these cats there is so
much virus in the effusion that all the antibody is bound to it,
and none is available to bind to virus in the test.)

Note:
many healthy cats and cats with diseases other than FIP have FCoV
antibodies. The presence of FCoV antibodies alone is NOT diagnostic
of FIP, if the other parameters of the profile do not indicate a
diagnosis of FIP.

Virus detection in macrophages by direct immunofluorescence or immunohistochemistry

Detection of FCoV in macrophages in an effusion by direct immunofluorescence is diagnostic of FIP, but a negative result is more difficult to interpret (Hartmann et al, 2003). This test is not currently widely available but should become available from the University of Glasgow in the UK soon.

Viral RNA detected by RT-PCR in the effusion

Reverse transcriptase polymerase chain reaction (RT-PCR) detects the RNA of the FCoV – i.e. is a test which detects actual virus. Quantitative RT-PCR (RT-qPCR) is an interesting recent development in which the amount of virus in the sample may be measured. RT-PCR is useful in control of FCoV infection in households of healthy cats and is useful in FIP diagnosis on organs of cats in biopsy or post mortem specimens.

Detection of FCoV RNA in the blood or faeces is not diagnostic of FIP, since some healthy FCoV antibody positive cats, or animals with non-FIP illness, are also positive. In addition, cats with FIP may be negative – the effusion of cats with FIP is often negative.

Summary
A cat with
wet FIP should be FCoV seropositive, the total protein of the effusion
must be over 35g/l and the albumin:globulin less than 0.4 (or at
least less than 0.8), the AGP should be high (over 1500 micrograms/ml)
and the cytology should reveal few nucleated cells which are mainly
neutrophils and macrophages. A Rivalta test should be positive. Diagnosis can be confirmed by detecting FCoV in the macrophages in the effusion.

If you understand that FIP is an immune-mediated vasculitis it becomes easier to understand how it is able to manifest with so many varied clinical signs. Any blood vessel to any organ can be affected and the clinical signs will result from damage to that organ. FIP is generally defined as either “wet” (effusive) or “dry” (non-effusive) but neither is clear cut and an effusive case can become non-effusive or vice versa. Effusive FIP is the more acute condition – occurring within 4-6 weeks of a stressful event in the cat’s life, whereas non-effusive FIP can incubate for months to years.

In the longer incubating non-effusive, FIP, fewer blood vessels are affected than in effusive FIP and the immune response is more chronic, leading to larger pyogranulomata. The cat loses weight gradually, is chronically pyrexic, and becomes dull and anorexic. Most cats with dry FIP have palpably enlarged mesenteric lymph nodes and intraocular lesions. Clinical signs will depend on which organs are involved:

if the liver is affected, the cat will be jaundiced (icteric)

if the meninges/hydrocephalus are affected, neurological signs (ataxia, nystagmus, fits, loss of reflexes) will occur

if the eyes are affected there will be uveitis, aqueous flare, vitreous flare, retinal vessel cuffing, corneal precipitates, haemorrhage into anterior or posterior chambers (see photographs above on this page)

Haematology reveals a non-regenerative anaemia and lymphopenia
In non-effusive
FIP there is lymphopenia, a mild non-regenerative anaemia with a haematocrit
of 30% or less and often a neutrophilia with a shift to the left.
Bear in mind that cats with other chronic infections can have similar
haematological changes. Haematology is useful in differentiating
FIP from Haemobartonella
felis infection where
the anaemia is regenerative and there may be organisms visible on
the erythrocytes.

Hypergammaglobulinaemia causing low Albumin:Globulin ratio
(A:G) ratio
In FIP
the globulin concentration in serum or plasma is raised to over
40g/l. Consequently the A:G is usually lowered. An A:G of < 0.4
indicates FIP is quite likely, provided that globulins are raised,
remember than a low albumin (e.g. in liver disease) can also artificially
lower the A:G. An A:G of >0.8 rules out FIP; A:G of between 0.4-0.8
- consider other parameters.

In addition, often bilirubin levels are raised, although other liver enzymes may be normal.

Note:
many healthy cats and cats with diseases other than FIP have FCoV
antibodies. The presence of FCoV antibodies alone is NOT diagnostic
of FIP, if the other parameters of the profile do not indicate a
diagnosis of FIP. A healthy cat with a high FCoV antibody titre
is NOT a cat with dry FIP.

AGP level AGP is an acute phase protein
which is useful in distinguishing FIP from other clinically similar
conditions. In FIP, AGP levels are usually greater than 1500 ug/ml.
In normal cats, it’s up to 500 ug/ml. Bear in mind, however, that
AGP is not specific, and will also be raised if there is viral (non-FIP),
bacterial (e.g. ascending cholangiohepatitis or pyelonephritis)
or fungal infections or recent trauma. AGP measurement is useful
in distinguishing FIP from neoplasia or non-infectious liver disease,
when AGP levels will be normal.

Reverse transcriptase polymerase chain reaction (RT-PCR) detects the RNA of the FCoV – i.e. is a test which detects actual virus. Quantitative RT-PCR (RT-qPCR) is an interesting recent development in which the amount of virus in the sample may be measured. RT-PCR is useful in control of FCoV infection in households of healthy cats and is useful in FIP diagnosis on organs of cats in biopsy or post mortem specimens.

Detection of FCoV RNA in the blood or faeces is not diagnostic of FIP, since some healthy FCoV antibody positive cats, or animals with non-FIP illness, are also positive. In addition, cats with FIP may be negative – the blood of cats with FIP is usually negative. In non-effusive FIP, detection of large amounts of virus in a fine needle aspirate of a mesenteric lymph node is highly indicative of FIP. However, detecting FCoV in the CSF of cats is not diagnostic – healthy cats and cats with non-FIP conditions are occasionally positive (detecting FCoV antibody in the CSF is more useful).

Summary A cat with dry FIP should have
a high FCoV antibody titre, be hyperglobulinaemic and have a reduced
albumin:globulin ratio. He or she should have a high AGP, lymphopenia,
a haematocrit of less than 30% which is non-regenerative and possibly
a neutrophilia. Clinically, the cat should have lost weight and
will usually have ocular signs such as iritis, retinal vessel cuffing,
keratic precipitates, aqueous or vitreous flare.

Remember:
a healthy cat with a FCoV antibody titre is NOT a cat with dry FIP.

This laboratory declined to take part in the assessment, however I paid to have a few tests examined - there were some false positive results given.

Italy

Italy boasts more than its share of FCoV experts:

AGP testing and immunofluorescence of macrophages in effusion - Prof. Saverio Paltrinieri is the world expert in feline alpha 1-acid glycoprotein (AGP) and he and his colleague developed the technique of direct fluorescence in macrophages in effusions

FCoV RT-PCR - Dr Nicola Decaro (this young man is the world expert in canine coronavirus!)

Drs Decaro and Pratelli are based at the University of Bari. The University of Bari laboratory uses their own quantitative RT-PCR for detection of coronavirus. They developed their own antibody ELISA cited in Pratelli et al, 2008 and Pratelli et al, 2009 and has the technology to do immunofluorescence, virus neutralisation testing and western blotting. They are also able to differentiate IgA and IgG. I highly recommend this laboratory.

This is the laboratory of world renowned FCoV/FIP expert Prof. Hans Lutz and is run by another expert and highly efficient scientist: Dr Marina Meli. It was in this laboratory that the first RT-qPCR to detect FCoV was developed. They also offer a TGEV indirect immunofluorescent antibody test.

Lucy Whittier Molecular and
Diagnostic Core Facility. This is the veterinary diagnostic laboratory of the legendary Dr Niels Pedersen - the number 1 world expert on FIP! He is also the man who discovered Feline Immunodeficiency Virus! You can download a sample submission form
from the website.

Virus
detection by RT-PCR See also What is RT-PCR. RT-PCR detects the FCoV genome,
so indicates presence of the virus. However, interpretation of such
tests is difficult: healthy cats as well as cats with FIP can be
positive for the virus. Also, cats with illnesses other than FIP can co-incidentally have the virus.

In my research survey, I
found that it was less useful to use RT-PCR than our antibody test:
to show that a cat has eliminated FCoV required only one antibody
titre of less than 10 in our laboratory, but required 5 monthly
negative RT-PCR tests on faeces. However, RT-PCR remains the only
way to detect a carrier cat - a cat who sheds FCoV continually for
9 months or more is likely to be a lifelong carrier.

At time of writing, there
is no RT-PCR which can differentiate FIP-causing coronaviruses from
coronaviruses which do not cause FIP. The difference between the
former and the latter is that in FIP, the FCoV can replicate in
macrophages, whereas in FCoV infected cats without FIP, FCoV is
not replicating in macrophages. (Replicate means multiply, macrophages
are a type of white blood cell.) However, at the Second International Feline Coronavirus/Feline
Infectious Peritonitis
workshop, a young Dutch scientist, Fermin Simons, presented an RT-PCR
he is working on which detects replicating FCoV in macrophages,
his abstract is on the SIFFS website. This RT-PCR is not presently
commercially available, but is a very promising test for the diagnosis
of FIP.

Any of the following clinical
signs should alert you to the possibility of your cat developing
FIP:

weight loss recurring fevers (usually detected when
your veterinary surgeon takes the cat's temperature) going off food the cat becomes even lazier
than usual
sudden swelling of the abdomen look closely at your cat's eyes regularly,
watch for any change in colour of the iris (the coloured area of
the cat's eye around the pupil) or any cloudiness, or bleeding (look
closely at the cats' eyes in the Dry or non-effusive FIP section to get an idea of what you are looking
for)
difficulty breathing (the cat breathing through his or her mouth) if the cat
has a fit or seizure if the cat seems to lose balance, become clumsy if the cat's
personality changes

If you are a cat breeder,
the following signs in your kittens should alert you to the possibility
of FCoV being present in your cats:

kittens of uneven size in a litter diarrhoea
in kittens around 5-7 weeks of age transient sneezing or discharge from the
eyes in young kittens

Remember that all of the
clinical signs described above can occur due to other, curable,
conditions, so take your cats to your veterinary surgeon to be checked
if any of these signs occur and hope for the best. Remember that
8 out of 10 cats whose samples were sent to our laboratory for FIP
diagnosis turned out not to have FIP at all!